E045029034

IOSR Journal Of Pharmacy
(e)-ISSN: 2250-3013, (p)-ISSN: 2319-4219
www.iosrphr.org Volume 4, Issue 5 (May 2014), PP. 29-34
29
Clostridium Difficile infection and Antibiotic –Associated Colitis
Murtaza Mustafa1
,Muhammad Iftikhar2
,Saima Shafi3
,Malik J.Shah4
1,2,4
Faculty of Medicine&,Health Sciences, University Malaysia Sabah,KotaKinabalu,Sabah,Malaysia
3
, Hospital Queen Elizabeth,Kota Kinabalu, Sabah, Malaysia
ABSTRACT:Hospitalized patients receiving β lactam antibiotics develop diarrhea and higher rates reported
in those receiving clindamycin. Clostridiumdifficile is recognized as a cause of antibiotic associated diarrhea,
colitis and pseudomembranous colitis. Contributory factors include: advance age, severity of underlying
illness.C.difficile has the ability to temporarily colonize newborn humans and calves, suggests that the
gastrointestinal tracts of young animals may be a major reservoir.C.difficile is recognized enteric pathogen in
animals including companion animals and food animals. Clinical features include: asymptomatic carriage in
neonates to a fulminant, relapsing, and occasionally fatal colitis. Initial therapy for pseudomembranous colitis
includes discontinuation of offending antibiotic regimen, fluid replacement and electrolyte losses. Mild to
moderate infection with metronidazole,severe to recurrent cases with vancomycinTherapy with probiotic such
as Sacchromyces boularadii is beneficial. Antibiotic misuse in humans and production animals must be
addressed.
KEY WORDS:Clostridium difficile, Antibiotic, Colitis, and Diarrhea
I. INTRODUCTION
Antibiotic associated diarrhea and colitis is most common complications of antibiotic therapy.Attack
rates vary depending on the antimicrobial agent used, the epidemiologic setting, and the host. Overall attack
rates antibiotic-associated diarrhea in hospitals rage from 3.2% to 29% [1].Almost 15% of hospitalized patients
receivingβ-lactam antibiotics develop diarrhea and rates for those receiving clindamycin rage from 10% to 20%
[2].Clostridium difficile is now recognized as a frequent cause of antibiotic associated diarrhea and colitis, and
the incidence of C.difficile associated diarrhea seems to be increasing [3].It is implicated in 20% to 30% of
patients with antibiotic-associated diarrhea, in 50% to 75% of those with antibiotic- associated colitis
[4].Literature from the mid-1970s emphasized that attack rates for diarrhea and pseudomembraneous colitis
associated with the use of individual antibiotics. Several studies rates of clindamycin and lincomycin associated
diarrhea ranging from 7% to 21% and rates of ampicillin-associated diarrhea from 4% to17% [5].In the late
1970s,a series of investigations established toxigenic C.difficile as the cause of pseudomembranous colitis
[6].The reported incidence of ofC.difficile in acute-care hospital increased from 30 to 40 cases per 100,000
population in 1990s to 84 per 100,000 by 2005 [7]. Although colonization with toxigenic C.diffiile occurs
frequently among residents of some extended-care and rehabilitation facilities symptomatic disease develops in
only a minority of infected patients [8].Animal studies found that intracecal materials transferred the disease
from affected hamsters to healthy ones that both the cultures of Clostridia and their cell-free supernatants
produced this disease and this activity was neutralized by gas gangrene antiserum [9].Ritkin and associates
reported that stool filtrates from the humans with pseudomembranous colitis were lethal for hamsters; caused
edema,hemorrhage, and increased vascular permeability in rabbit skin and possessed cytotoxic activity that was
neutralized by Clostridium sordelli antitoxin [10]. Emergence of strains causing C.difficile infection in the
community (CA-CDI) is becoming more commonplace [11].Unlike health care infections, CA-CDI is associated
with younger, healthy people, often without prior exposure to antimicrobials or contact with hospitalized
patients [12].The rates of human infection CDI have increased dramatically and C.difficile is recovered from
Australian production animals [13,14].The paper reviews pathophysiology, clinical features, diagnosis and
therapy of antibiotic associated colitis.
II. PATHOPHYSIOLOGY
C.difficle most often causes a nonspecific colitis.However, especially in more severe cases, one may see the
distinct macroscopic appearances of pseudomembranous colitis. The colonic mucosa is studded with
adherent,raised,white and yellowish plaques.Initially,these lesions are small and discrete and are easily
dislodged; the intervening mucosa may be inflamed and covered with mucus, but often it appears entirely
normal [15].With progression of disease, pseudomembranous plaques may enlarge and coalesce. Pseudo-
membranes can exist throughout the entire colon, but they are usually most pronounced in the recto sigmoid

Clostridium Difficileinfectionand Antibiotic -----
30
colon; rarely does the disease progress proximal to the ileocecal valve [15].Histological criteria for
pseudomembranous colitis and method for grading lesions have been described. The principal features are
inflamed mucosa with a neutrophil predominance and mucin distended glands. Attached pseudomembranous are
composed of a loose network of mucin, neutrophils, fibrin, and nuclear debris [15].
III. RESERVIORS OF INFECTION
Researchers have documented the prevalence of C.diffficile (or one of its toxins) in 15% to 70% of
neonates [16].Despite the presence of toxin-producing organisms in this population, the prevalence of C.difficile
colitis remain low [17].Enhancement of chemotactic responses of granulocytes to toxin A in older persons and
the absence of high-affinity receptors for toxin A in neonates (in a rabbit model) have been cited as possible
reasons for this age-dependent susceptibility [18,19]. The ability of C.difficile to temporarily colonize newborn
humans, hamsters,and calves suggests that the gastrointestinal tract of very young mammals may be a major
reservoir [19,20].In healthy adults, intestinal carriage rates of toxigenic C.difficle are typically 3% or less and
not greater than 8%.Asymptomatic intestinal carriage rates are higher (-approximately 20%) among hospitalized
adults, particularly those who have received antibiotics [21,22].
C.difficile is a recognized enteric pathogen in a variety of animals including companion animals e.g.
Cats dogs,horses, and food animals (cattle,sheep,goats,pigs)[23].In Australia C.difficile has been isolated from
piglets,sheep,lambs,horses,cats,digs and cattle with the highest prevalence in neonatal animals due to a lack of
established gut flora at birth. For this reason predisposing antibiotics may not be required for development of
CDI in young animals although there is anecdotal evidence in Australia of routine use of extended-spectrum
cephalosporins in production animals. This is particularly concerning in the pork industry where gross
contamination of facilities with C.difficile spores is commonplace with C.difficile [24]. Several meat products,
seafood, ready–to eat salad leaves and vegetables are also contaminated with C.difficile, predominantly ribotype
078-like strains [16].Contamination may occur through spillage of gut contents at slaughter or direct
contamination by food handlers during dressing or retailing. Environmental contamination may also play a role.
C.difficile spores survive in treated piggery effluent, the byproducts of which are often applied to agriculture
land, used in retail compost manufacture, or recycled within swine facility [25].
Outside Australia, the increasing prevalence of PCR ribotype 078 in humans, food production animals
and food products suggest potential zoonotic transmission. In Netherlands,where infections with ribotype 078
increased more than fourfold from 2005 to 2008.patients infected with this ribotype were younger and acquired
C.difficile in the community more frequently particularly if they lived in rural pig producing areas [26]. In the
USA,the prevalence of ribotype 078 infections in humans increased from 0.02% to 1.3%(pre 2001 to 2006) and
ribotype 078 is increasingly associated with CA-CDI.These strains are indistinguishable or very closely related
to animal ribotype 078 strains by PFGE analysis [27].Ribotype 078 strains from Dutch humans and pigs are
indistinguishable by MIVA subtyping [28].Transmission from humans to animals may occur.C.difficile can be
isolated from the feces of hospital pet therapy dogs that had prior negative culture for C.difficile.These dogs
were > 2 times likely to be colonized with C.difficile than dog’s not vising hospital [29].
IV. EXASPERATE AGENTS
Almost all antibiotic classes have been associated with the disease, reports of large clinical series’ most
commonly implicate clindamycin,penicillins,cephalosprins and more recently fluroquinolones [30].Several
noteworthy studies primarily implicated clindamycin and ampicillin in the 1970s [31].In the most recent
outbreaks associated with NAPI/027 (North American pulsed field type 1, ribotype027) which is resistant to
fluoroquinolones,fluoroquinolones are clearly identified as a risk factor for clinical disease [32].Third
generation cephalosporin’s have been implicated in particular and seem to predispose to C.difficile-associated
disease more commonly than do the narrow spectrum penicillin’s or β-lactam-stable penicillin [33].A number of
antineoplastic agents particularly those with modest antibacterial activity,have been associated with C.difficile
diarrheal disease, including doxorubicin, cisplatin,cyclophosphamide and others [34 ].
V. CONTRIBUTORY FACTORS
Antimicrobials use is the primary factor in the disease, but certain host and environmental factors also
predispose to C.difficile-associated disease. In a comprehensive prospective study of risk factors in hospitalized
patients, McFarland and associates[35], identified advance age and severity of underlying illness as factors
associated with increased risk of C.difficile carriage and diarrhea and found that agents that alter normal
intestinal motility-specifically enemas and gastrointestinal stimulants, as well as stool softener-also contribute to
the risk of C.difficle associated diarrhea [35].Given the tendency of this disease to affect ill elderly patients who
receive antibiotics, it is no surprise that patients with C.difficile are also at risk of colonization by vancomycin
resistant enterococci [36].Other investigators have reported that critically ill burn patients, uremic patients,
patients with hematologic malignancies, and those undergoing gastrointestinal surgery are at high risk of

31
C.diffiile diarrhea and colitis [37-40].Emerging evidence suggests that immunologic susceptibility may play a
critical role in C.difficile-associated infection. Host immunoglobulin G responses have been shown to protect
against symptomatic disease and relapse [41,42].Human deficiency virus (HIV) infection per se does not appear
to predispose to C.difficile colonization and specific risk factors for C.difficile- associated disease among HIV-
infected patients appear to be similar to those HIV seronegative persons [43,44].In recent years CA-CDI has
become more common, and in nearly one fourth of such cases, no traditional risk factor are identified [45]
VI. CLINICAL FEATURES
Infection with toxigenicC.difficile causes a spectrum of disease ranging from asymptomatic carriage
(particularly in neonates) to a fulminant, relapsing, and occasionally fatal colitis. When C.difficile produces
clinical disease, the onset of signs and symptoms typically occurs after 3 to 5 days of antibacterial treatment, but
diarrhea may develop as early as first of therapy or as late as 10 weeks after cessation of therapy [46].C.difficile
diarrhea may be brief and self-limited or it may be cholera like, resulting in more than 20 stools per day
[2].Accompanying findings often include fever (30% to 50% of patients), leukocytosis (50% to 60%) and
abdominal pain or cramping (20% to 33%) [47,48,47].The mean peripheral leukocyte count of patients with
C.difficile-associated diarrhea typically 15,000 to 16,000/mm3
in one series.C.difficle infection was noted in 25%
of patients with white cell counts of greater than of greater than 35,000/mm3
who did not have hematologic
malignancy [49].Nausea, malaise,anorexia, hypoalbuminemia,occult colonic bleeding, and dehydration have
also been reported [2].Infrequently,C.difficile colitis manifests without diarrhea as an acute abdominal syndrome
or toxic megacolon [50].In one report,5 of 97 patients with C.difficile disease(only 1 of whom had profuse
diarrhea) presented initially with marked leukocytosis (white cell count>25,000/mm3
) and right lower quadrant
peritoneal signs mimicking those of acute peritonitis [51].Toxicmegacolon is suggested by acute dilatation of
colon to a diameter greater than 6 cm, associated systemic toxicity, and the absence of mechanical obstruction.
It carries a high mortality rate (64% in one series of 11 patients) [52].Other intra-abdominal complications
include colonic perforation, transverse volvulus, protein-losing enteropathy, and recurrent C.difficile–associated
diarrhea, the last occurring in approximately 20% of patients [53,54,55].Extra intestinal manifestation occur
more rarely and include bacteremia, often with concurrent isolation of other constituent organisms in the bowl
flora, splenic abscess, and osteomyelitis[56,57,58].In addition, multiple reports have described reactive arthritis
or tenosynovitis or both [59,60].
Consideration in the differential diagnosis of antibiotic-associated colitis include diarrhea caused by other
enteric pathogens [especiallySalmonella), adverse reactions to other medications, ischemic colitis, inflammatory
bowel disease, and intra-abdominal sepsis [50].
VII. DIAGNOSTIC METHODS
C.difficile-associated disease should be suspected in patients with diarrhea who have received
antibiotics within the past two months or whose diarrhea begins 72 hours after hospitalization [50].In most
instances, toxin testing or C.difficile culture of a single stool specimen effectively establishes the diagnosis;
however, repeat testing or endoscopy, or both may be necessary
C.difficile toxin detection
The most widely used means of diagnosing C.difficile-associated diarrhea and colitis clinically
detection of C.difficile toxin in stool specimens. The cytotoxicity assay has been considered the gold standard
for diagnosis, but most clinical laboratories use various enzyme immunoassays, which perform reasonably well
compared with cytotoxicity assays [6].Stool filtrate are incubated with mammalian tissue culture cell line with
and without toxin-neutralizing antibody. If toxicity activity, usually manifested as surrounding of cultured cells,
is noted in the well with stool filtrate and toxin-neutralizing antibody, the test for the specimen is considered to
be positive [6].If used in appropriate clinical setting, this test is both sensitive and specific; more than 90% of
patients with pseudomembranous colitis have cytotoxicity in their stool detected by this assay [61].
C.difficile toxin A or B can be detected by enzyme-linked immunobsorbent assay kits, available commercial
kits, their performance characteristics have been studied extensively [62].In general, they are rapid, relatively
inexpensive, and specific, but lack the sensitivity of the technically more cumbersome cytotoxin assays.If
measured against strictest diagnostic criteria that include clinical diarrhea, along with cytotoxin assay and
culture results, their sensitivity rages from 63% to 94 % with a specificity of 75% to 100% [63].
C.difficledetection by culture
Anaerobic culture forC.difficile,the most sensitive test in many laboratories, remains essential
for epidemiologic studies of outbreaks.However, cost and convenience issues have driven many hospital
laboratories to replace routine cultures with more rapid and less expensive enzyme-linked immunosorbent assay
based assays, sometimes in combination with cytotoxinassays. Most clinical microbiology laboratories are not

32
equipped to distinguish between nonpathogenic, on toxigenic strains, and testing schemes that rely solely om
C.difficile cultures yield a significant number of false-positive results (In some hospitals, 20% to 25% of
C.difficie isolates are non-toxigenic [64].Testing for stool toxin simultaneously or using in vitro toxin
production assays my help to resolve this problem [63].
Endoscopy for detection of pseudomembrane
The detection of exudative plaques or pseudo membranes on colonic mucosa establishes the diagnosis
of pseudomembranous colitis. The pathognomonic lesions is characteristically raised, yellowish, and usually 2
to 10 mm in diameter with “skip” of normal mucosa, but in severe disease, lesions may coalesce to form plaques
[50].At least 90% of patients with pseudomembranous colitis demonstrate either C.difficile or its toxin in stool
samples [48].Because of its cost, risk to the patient, and availability of other diagnostic tests, endoscopy is
usually reserved for special situations [50].
VIII. THERAPY
Treatment of choice in Clostridium difficile-associated diarrhea and colitis for adults include: Initial
therapy for pseudomembranous colitis should commence with discontinuation of the offending antibiotics
regimen, if possible, and replacement of fluid and electrolyte losses. In a prospective treatment trial the diarrhea
resolved before initiation of therapy in 23% of 149 patients, but most patients require specific antibacterial
therapy [65].Therapy of Clostridium difficile-associated diarrhea and colitis for adults begins with replace fluid
and electrolytes, if clinical situations allows, discontinue offending antibiotic, and avoid antiperistaltic agents
plus for mild to moderate infection metronidazole 500 mg orally 3 times daily for 10 to 14 days.In severe
infection or unresponsiveness to or intolerance to metronidazole, vancomycin 125 mg daily 4 times daily for 10
to 14 days. For second recurrence,vancomycin in tapered and pulsed doses a) 125 mg 4 times daily for 14 days,
b)125 mg orally twice daily for 7 days, c)125 mg once daily for 7 days, d) 125 mg orally once every 2 days for
8 days)125 mg once every 3 days for 15 days [15].Other options for recurrent infection include:Vancomycin
followed by rifamiximin,400 mg orally 2 times daily for 14 days. Therapy with probiotic such as Sacchromyces
boulradii[15].
Antiperistaltic agents, such as loperamide and diphenoxylate hydrochloride with atropine should be
avoided. There is little evidence that such agents lead to symptomatic improvement, and in one study predating
the discovery of Clostridumdifficile as a pathogen, diarrhea was actually more common among those receiving
diphenoxylate-atropine plus lincomycin than those receiving placebo plus lincomycin [66].Several ancedotes
and case series have associated the use of diphenoxylate and of lapromide and other anti-peristaltic agents with
the development of toxic mega colon in patients with C.difficiledisease or pseudomembranous colitis [51].
IX. CONCLUSION
Diarrhea and colitis is most common complications of antibiotic therapy.C.difficle causes diarrhea in
humans and animals. Toxigenic C.difficleis also cause of pseudomembranous colitis.CA-CDI strains causing
infection in the community is also common.Antimicrobial use in humans and animals must be addressed.
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